Neuropeptide Signaling Activates Dendritic Cell-Mediated Type 1 Immune Responses through Neurokinin-2 Receptor

Abstract

Neurokinin A (NKA), a neurotransmitter distributed in the central and peripheral nervous system, strictly controls vital responses, such as airway contraction, by intracellular signaling through neurokinin-2 receptor (NK2R). However, the function of NKA–NK2R signaling on involvement in immune responses is less-well defined. We demonstrate that NK2R-mediated neuropeptide signaling activates dendritic cell (DC)-mediated type 1 immune responses. IFN-γ stimulation significantly induced NK2R mRNA and remarkably enhanced surface protein expression levels of bone marrow-derived DCs. In addition, the DC-mediated NKA production level was significantly elevated after IFN-γ stimulation in vivo and in vitro. We found that NKA treatment induced type 1 IFN mRNA expressions in DCs. Transduction of NK2R into DCs augmented the expression level of surface MHC class II and promoted Ag-specific IL-2 production by CD4+ T cells after NKA stimulation. Furthermore, blockade of NK2R by an antagonist significantly suppressed IFN-γ production by both CD4+ T and CD8+ T cells stimulated with the Ag-loaded DCs. Finally, we confirmed that stimulation with IFN-γ or TLR3 ligand (polyinosinic-polycytidylic acid) significantly induced both NK2R mRNA and surface protein expression of human PBMC-derived DCs, as well as enhanced human TAC1 mRNA, which encodes NKA and Substance P. Thus, these findings indicate that NK2R-dependent neuropeptide signaling regulates Ag-specific T cell responses via activation of DC function, suggesting that the NKA–NK2R cascade would be a promising target in chronic inflammation caused by excessive type 1-dominant immunity.

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells

“…3 Moreover, we found that the NKA-NK2R signaling pathway was involved in the antigen-presenting function of murine dendritic cells (DCs) and that NK2R expression on DCs was enhanced by Ohtake 8 IFN- and LPS stimulation in a STAT-1-dependent manner. 4 Additionally, we confirmed that human DCs significantly upregulated gene expression levels of NK2R and TAC-1, which encoded Substance P and Neurokinin A, after IFN- or poly I:C stimulation, suggesting possible roles of neuropeptide signaling in human DCs. 4 In this study, we investigated the effects of neuropeptide signaling through NK2R as well as NK1R on antigen presentation by human DCs and the subsequent activation of effector Th cells.…”

“…4 Additionally, we confirmed that human DCs significantly upregulated gene expression levels of NK2R and TAC-1, which encoded Substance P and Neurokinin A, after IFN- or poly I:C stimulation, suggesting possible roles of neuropeptide signaling in human DCs. 4 In this study, we investigated the effects of neuropeptide signaling through NK2R as well as NK1R on antigen presentation by human DCs and the subsequent activation of effector Th cells.…”

Neuropeptide substance P and the immune response

“… (1)(Jeon et al, 1999; Kavelaars et al, 1994; Voedisch et al, 2012), (2)(Janelsins et al, 2009; Janelsins et al, 2013; Takashima, 2013), (3)(Barros et al, 2011; Cunin et al, 2011), (4)(Sun et al, 2008a), (5)(Kitamura et al, 2012), (6)(Asahina et al, 1995b; Carucci et al, 2000; Fox et al, 1997; Hosoi et al, 1993; Mikami et al, 2011; Nong et al, 1989; Rochlitzer et al, 2011; Voedisch et al, 2012), (7)(Asahina et al, 1995a; Liu et al, 2000; Mikami et al, 2011; Mikami et al, 2014), (8)(Ding et al, 2008; Mikami et al, 2011; Takashima, 2013), (9)(Takashima, 2013), (10)(Mikami et al, 2012), (11)(Lipton & Catania, 1997; Luger et al, 2003; Star et al, 1995), (12)(Taylor et al, 2000), (13)(Takashima, 2013), (14)(Namba et al, 2002; Takashima, 2013; Taylor & Namba, 2001; Taylor, 2003; Taylor et al, 2000), (15)(Delgado et al, 2005b; Delgado et al, 1999b; Delgado et al, 2004b; Voedisch et al, 2012), (16)(Delgado et al, 2005b; Delgado et al, 1999c; Goetzl et al, 2001), (17)(Delgado et al, 2004a; Delgado et al, 2002; Delgado et al, 1999a; Takashima, 2013; Voice et al, 2004), (18)(Delgado et al, 2005a; Gonzalez-Rey et al, 2006a; Gonzalez-Rey et al, 2006b; Takashima, 2013), (19)(Jimeno et al, 2015; Yadav & Goetzl, 2008) …”

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…Although the effects of neuropeptides on DC generation, function and longevity have been repeatedly reported [85][86][87], including the effects of tumor cell-derived neuropeptides [88], the role of DC-derived neuropeptides in immune response regulation was not well determined. However, neuropeptides might be involved in functional activity of regDC in the inflammatory and probably tumor microenvironment.…”